Multiple neurochemical systems degenerate in PD, and several common and profoundly disabling symptoms are largely levodopa resistant. Progressive gait and balance difficulties, and associated falls, are among the most common levodopa resistant symptoms, eventually occurring in nearly all patients. The gravity of this problem is underscored by a lack of any effective therapy, leading the authors of the NINDS PD 2014 Research Report to list as highest priority recommendations studies aimed at understanding the neural circuit mechanisms of gait and balance disorders in PD, and developing effective treatments for these dopa-resistant symptoms (Clinical recommendations 2, 3 & 4; Translational recommendation 1 & 6; Basic recommendation 3). Our team has made a series of discoveries in human subjects with PD and in a novel PD animal model that strongly implicate degeneration of cholinergic projections in the pathogenesis of gait dysfunction in PD. The central themes of the proposed University of Michigan (U-M) Udall Center research program are the role of cholinergic lesions in gait and balance abnormalities in PD and the development of novel treatment strategies targeted at cholinergic neurotransmission. Considerable recent data indicates that gait and postural control are not purely motor functions but require complex integration of motor, sensory, and cognitive functions. Defining the relationship between cholinergic dysfunction and gait abnormalities requires a multidisciplinary approach in which investigators view the relationship between cholinergic function, gait, and cognition through different lenses, share insights and challenge each other in ways that yield progress far beyond that achievable were each project pursued separately. We have assembled such a team, making our proposed work ideally suited for support under the P50 Udall Center mechanism. Our team has developed preliminary data that lead us to propose a 3-Hit model of gait dysfunction in PD which posits that the typical clinical progression of gait and postural abnormalities in PD is caused by the interaction of striatal dopamine loss with degeneration of cholinergic neurons in the basal forebrain (BF) and pedunculopontine (PPN) nucleus. The proposed research program will test the 3-Hit hypothesis and seek to develop proof-of-principle evidence for a novel cholinergic-based therapy for falls in PD. Project I will further develop and mechanistically dissect a recently published unique rodent model of PD gait abnormalities mimicking the combined cholinergic and dopaminergic lesions that occur in PD. These studies will define the cognitive-motoric impact of loss of PPN cholinergic neurons, alone and in combination with BF cholinergic and striatal dopaminergic loss and, in connection with Project III, examine the therapeutic benefit and circuit mechanism of action of stimulation of a defined molecular target (?4?2* nicotinic receptors). Project II will employ a novel PET ligand in PD patients that provides previously unattainable resolution of cholinergic nerve terminals; this ligand will enable, for the first time, delineation of PPN cholinergic projections that have been implicated in gait abnormalities in PD. Our preliminary data demonstrate that PD patients exhibit considerable heterogeneity of cholinergic degeneration, suggesting the presence of subgroups that may exhibit unique responses to pharmacological interventions. Utilizing a personalized medicine approach assessing only hypo-cholinergic subjects identified in Project II, Project III will employ novel PET and gait assessment methods in pilot target engagement/pharmacodynamic studies assessing the therapeutic potential and mechanism of action ?4?2* nAChR stimulation. This innovative approach is critical for a highly heterogeneous disease like PD. The proposed research program is synergistic with the Pacific Northwest Udall Center, two members of which are consultants for our proposed Center, and is supported by Administrative, Clinical Resource, and Biostatistics and Data Management Cores. Our proposed Center is also strongly committed to educating researchers, PD caregivers, PD patients and their families, and to pursuing outreach to traditionally underserved communities that suffer disproportionally from PD. These activities will be shared by the Administrative Core and an Education and Outreach Core, which will undertake joint educational activities with the University of Pennsylvania Udall Center, further integrating the Udall Center network. Together, our innovative approaches will provide much needed insight into a devastating yet understudied symptom of PD and advance the goal of the NINDS Udall Centers of Excellence program to define the causes of and discover improved treatments for PD. No current Udall Center is focused on gait and postural abnormalities in PD, or on cholinergic deficits. The proposed U-M Udall Center will therefore play a unique and important role within the NINDS Udall Center program.